(1) Current situation of depsipeptide and related materials:
The depsipeptide is a polymer or an oligomer in which a main chain is composed of ester bonds and amide bonds as represented in Formula (A). The skeleton of the structure is formed of amide bonds and ester bonds.

The amide bond and the ester bond contained in the skeleton have been known to have three kinds of interactions at a molecular level. That is, between amide bonds, the intramolecular and intermolecular hydrogen bonds cause a strong interaction and stabilization of the molecular structure. Accordingly, macroscopically, insolubilization to a solvent and improvement of mechanical strength are expected. In addition, between ester bonds, there is no intermolecular and intramolecular interactions by a hydrogen bond at a molecular level. Accordingly, macroscopically, flexibility or weakness due to decrease in mechanical strength is expected. That is, between the amide bond and the ester bond, a relatively weak intramolecular and intermolecular hydrogen bond between an oxygen atom in the ester site and NH in the amide site causes a structural stabilization of the molecular structure at a molecular level. Accordingly, macroscopically, a little improvement of the mechanical strength is expected as compared to the case of only amide bonds. Therefore, the depsipeptide can be used as a material having characteristics of an oligomer or a polymer formed of an amino acid and a hydroxycarboxylic acid. That is, a material having wide range of properties can be synthesized by changing the kinds, the compositions, and the sequences of the amino acids and the hydroxycarboxylic acids. Further, as advantages of the depsipeptide, the following three points are given: the depsipeptide hardly causes inflammation in a body; the depsipeptide can be used as a delivery material for a substance susceptible to an acid component; and a molded product of the depsipeptide has extremely high strength due to intermolecular or intramolecular interaction such as a hydrogen bond and a hydrophobic interaction. Thus, the depsipeptide is an extremely attractive substance.
Various studies have been actually conducted with respect to the polydepsipeptide. For example, it has been known that, when the side chain of the hydroxycarboxylic acid in the polydepsipeptide is changed to H—, CH3—, (CH3)2CH—, or (CH3)2CH—CH2— so that the hydrophobicity and the size of the steric hindrance are changed, the degradation rate in an organism can be adjusted within the wide range of 2 weeks to 6 months. In addition, the polydepsipeptide is characterized in that no inflammation is recognized in the joining surface with an organism tissue (Non-Patent Document 1).
There is no inflammation with the polydepsipeptide, but in general, it has been known that, when the degradation rate of a material using only polyhydroxycarboxylic acid is high, an inflammation reaction is easily caused (Non-Patent Document 2). This may be because a relatively strong acid component such as lactic acid or glycolic acid is accumulated. On the other hand, in case of polydepsipeptide, it is conceivable that the acid component is not accumulated because the polydepsipeptide produces a depsipeptide oligomer as a degradation substance, and no inflammation was found even at a high degradation rate.
The polydepsipeptide has been improved in recent years from the viewpoint of a synthesis method. For example, there are studies on reduction in the number of reaction steps. That is, it has become possible to produce a didepsipeptide by reacting, using an aminopyridine compound as a catalyst, a carboxyl group in an amino acid having a protected amino group with a hydroxyl group in a hydroxycarboxylic acid having a carboxylic group without protection (Patent Document 1 and Non-Patent Documents 3 and 4). By those studies, a depsipeptide having a repeating sequence has been successfully produced more easily without forming a protecting group of the carboxyl group in the hydroxycarboxylic acid. That is, even with a synthesis facility in a laboratory (several milliliters to several hundreds of milliliters), it has become possible to synthesize at once a pure polydepsipeptide in a unit of several hundreds of milligrams to several grams. In case where the scale is expanded to plant facilities (several liters to several hundreds of liters), the polydepsipeptide can be produced in a unit of several kilograms.
(2) Current situation of temperature responsive material:
In recent years, studies on temperature responsive materials which aggregate with the increase in the temperature have attracted attentions. The temperature responsive materials are expected to be applied to, using a property of containing much water, a drug delivery substance, a wound dressing material, an artificial muscle, a microcapsule, a biomachine, a biosensor, a separation membrane, and the like.
According to a method using a depsipeptide as well, temperature responsive materials have been developed in recent years (Patent Document 2 and Non-Patent Document 5). For example, depsipeptide polymers having repeating units of -Gly-Val-Gly-Hmb-Pro-(SEQ ID NO: 2) and -Gly-Val-Gly-Hmb-Ala-Pro-(SEQ ID NO: 3) (Hmb=valic acid residue) are disclosed. Those depsipeptide polymers are characterized by including a β-branched hydroxycarboxylic acid called valic acid (Hmb). This is because, in the position of the valic acid in the sequence represented herein, a β-branched amino acid (or hydroxycarboxylic acid) may be required for expression of the temperature responsiveness.
In the temperature responsive material formed of a depsipeptide or a peptide, it has been considered that the role of the β-branched amino acid is to cause a reversible temperature responsiveness by the following mechanism: by heating, water molecules subjected to hydrophobic hydration in ValγCH3 (or HmbγCH3) and ProδCH2 liberate from a side chain due to increase in molecular movement by heat energy and a hydrophobic interaction among side chains is caused (aggregation phenomenon of increased temperature responsiveness); and the reverse process is caused (dissolution phenomenon of decreased temperature responsiveness) (as examples of Val residue, Non-Patent Documents 6 to 9) (as examples of Ile residue, Non-Patent Document 10).
In the temperature responsive material formed of a peptide, it has been pointed that, in the case where an alanine residue but not the β-branched amino acid is used, the material shows an irreversible temperature responsiveness and becomes insoluble to water immediately (Non-Patent Document 11). That is, in the conventional temperature responsive material, it is necessary to introduce the β-branched amino acid into a determined position, and thus the conventional temperature responsive material has had a problem in a strict restriction in the sequence.
The hydroxycarboxylic acids that have been actually sold in the market in the past as biomaterials contain mainly lactic acid and glycolic acid as constituent components. These are excellent because there are many examples for use of the components, and advantages and disadvantages thereof are known.
On the other hand, the temperature responsive material formed of a depsipeptide up to the present uses valic acid (Hmb) as another hydroxycarboxylic acid. The valic acid is contained in many natural products as antibiotic substances, thereby being expected to have little problems. However, there are a few cases where the valic acid is used as a biomaterial. Therefore, there has been a problem in that many examinations including an examination about disposition may be necessary to apply the temperature responsive polymer containing valic acid (Hmb) to an organism.
As an interesting study, a polydepsipeptide sequence involved in the temperature responsive material was reported in 1990 (Non-Patent Documents 12 and 13). In the documents, polymers having two kinds of repeating sequences of -Val-Pro-Gly-Hmb-Gly (SEQ ID NO: 4) and -Val-Ala-Pro-Gly-Hmb-Gly- (SEQ ID NO: 5) was reported. The polymers had problems in the following four points: a temperature responsiveness was not exhibited; there were many synthesis steps; most important reaction called condensation reaction, in which an ester bond or an amide bond is produced, was a low-yield reaction (five reactions were described and respective yields were 23, 33, 54, 70, and 76%); and only 10 mg of a polymer as a final product was obtained as a result of the low yield. Actually, it is notable that the document described how difficult the synthesis of the sequence was.
That is, except for cases which the inventors of the present invention reported (Patent Document 2 and Non-Patent Document 5), up to the present, it has been generally considered that it is extremely difficult to synthesize the sequence of a polydepsipeptide and an oligodepsipeptide involved in the temperature responsive material and the synthesis is not practical.
Patent Document 1: JP 2004-269462 A
Patent Document 2: WO 2006/043644A1
Non-Patent Document 1: Yoshida et al., Journal of Biomedical Materials Research, 1990, Vol. 24, page 1173
Non-Patent Document 2: Yasuo Shikinami, Rheumatology, 1999, Vol. 21 No. 3, page 267
Non-Patent Document 3: Katagai et al., 2004, Vol. 73, page 641
Non-Patent Document 4: Oku et al., Acta Crystallographica Section E, 2004, Vol. E60, page 927,
Non-Patent Document 5: Nanasato et al., Peptide Science 2004, 2005, page 633
Non-Patent Document 6: Chan et al., Journal of Biomolecular Structure and Dynamics, 1989, Vol. 6, page 851
Non-Patent Document 7: Urry et al., Biochemistry and Biophysics Research Communication, 1977, Vol. 79, page 700
Non-Patent Document 8: Urry et al., Biopolymers, 1989, Vol. 28, page 819
Non-Patent Document 9: Urry et al., Progress in Biophysics and Molecular Biology, 1992, Vol. 57, page 23
Non-Patent Document 10: Urry et al., Biopolymers, 1986, Vol. 25, page 1939
Non-Patent Document 11: Rapaka et al., International Journal of Peptide and Protein Research, 1978, page 81
Non-Patent Document 12: Arad & Goodman, Biopolymers, 1990, Vol. 29, page 1633
Non-Patent Document 13: Arad & Goodman, Biopolymers, 1990, Vol. 29, page 1651